Friday, January 28, 2011

Diagram showing principal systems of association fibers in the human brain. The superior longitudinal fasciculus (SLF) is labeled at the center top (marked by purple arrows).

New Scientist covered two journal articles by Rametti and colleagues (2010, 2011), a group of Spanish researchers and clinicians affiliated with Unidad Trastorno Identidad de Género[Gender Identity Disorder Unit]. Using the diffusion tensor imaging (DTI) method, they initially wanted to identify any sex differences in the white mater of the brains of non-transgendered male and female heterosexuals. Then the next step was a prediction that FTM (Female-to-Male) transsexuals would be more like males, while MTF (Male-to-Female) transsexuals would be more like females.

Differences in the brain's white matter that clash with a person's genetic sex may hold the key to identifying transsexual people before puberty. Doctors could use this information to make a case for delaying puberty to improve the success of a sex change later.

In 5 years of writing this blog, I have come across a multitude of news stories and press releases that make outrageous claims. Here's another one to add to the list. On the basis of two highly variable DTI studies in 36 pre-operative, pre-hormone treatment transgender individuals, now we're supposed to screen children for gender variant behavior and scan them at a young age, so their hormones can be altered before puberty?

Returning to the structural imaging experiments, were there any hypotheses at the outset, or were these completely exploratory studies? The authors cite the work of Zhou et al. (1995) on postmortem staining of the bed nucleus of the stria terminalis (BST). This subcortical nucleus connects the amygdala to the septal nuclei, hypothalamus, and thalamus. BST has been shown to play a role in the sexual behavior of male rats. The size of this nucleus in MTF brains was similar to that in female controls, both being smaller than male controls.

However, it's not possible to visualize the BST in living humans, so the authors went with DTI to look for cortical white matter changes. The participants in the first study were 18 FTM transgendered persons (before undergoing hormonal treatment), along with 24 male and 19 female heterosexual controls. The major findings in terms of sex differences between groups were located mainly in 3 fiber tracts:

In all 3 tracts, males showed higher fractional anisotropy (FA) than females. FA is a measure of local tissue properties including density, coherence, diameter, and myelination.

Fig. 1 (Rametti et al., 2010). Sex differences in fractional anisotropy (FA). FA is lower in female than in male controls in the superior longitudinal fasciculus with a posterior (A) and anterior (B) predominance. Control females also show lower than control male FA values in the forceps minor (C) and the corticospinal tract (D). The group skeleton used for the between group contrast study is green. The red color shows the clusters of significantly decreased FA in female compared to male controls. The threshold for significance was set at p < 0.05 corrected for multiple comparisons.

FTM individuals showed greater FA values in all 3 tracts than did the control females. They were similar to control males for anterior and posterior SLF and forceps minor, and in between control male and female FA values for the corticospinal tract.

What does this mean? Basically, at this point, it's like reading tea leaves. We have no indication of other potential differences between the groups in cognitive, emotional, personality, or motor measures, in alcohol use, or in other psychiatric diagnoses. We do know that testosterone levels of the FTM participants were like those of control females, because they had yet to undergo hormone treatment.

Moving right along to the second experiment, which compared MTF individuals to controls (Rametti et al., 2011)... The participants were 18 untreated MTF transsexuals (mean age = 25 yrs), 19 female (mean = 33 yrs) and 19 male controls (mean age = 32 yrs). Yes, the MTF individuals were significantly younger than controls [the human frontal lobe in particular is known to continue maturation processes into the 20's]. Procedures were similar to those used previously. Results in this study showed a greater number of differences in the white matter of male vs. female controls (again, with larger FA values for males):

left and the right SLF

forceps minor

right inferior front-occipital fasciculus (IFOF)

corticospinal tract

left cingulum

So what's new in this list? Left SLF, Right IFOF, Left cingulum. This finding indicates that individual differences were observed between two groups of male and female control subjects [or else there were unreported methodological differences]. If normal sex differences in DTI studies include IFOF and cingulum here but not there, that presents a problem for comparison to the transgendered populations.

Nonetheless, what did that comparison show? The MTF individuals showed FA values between those of male and female controls for all tracts (except for IFOF, where they did not differ from males).

Fig. 2 (Rametti et al., 2011). Histograms showing the FA means between control females (black), male to female transsexuals (MtF) (red) and control males (green). MtF transsexuals significantly differed from female and male controls in almost of all the fascicles in which control males differed from control females. (*At least p< 0.01).

So the MTF participants showed an intermediate pattern, but FTM individuals were more like biological males. The authors state:

Considering the present work and the data available in the literature, what can we say of the brain of MtF transsexuals? Most importantly, we would suggest that MtF transsexuals do not show a simple feminization of their brain –rather, they present a complex picture in which feminization and incomplete masculinization are present depending on the brain region studied and the kind of measurements taken.

So don't scan your little football-playing tomboy or haute couture-loving son just yet...

In the end, I don't doubt that there are differences between the brains of transgendered and non-transgendered people. But these two DTI studies1 do not provide a rationale for initiating treatments in young children.

Monday, January 24, 2011

Dr. Janusz K. Rybakowski, a Polish psychiatrist, published a brief report in the Journal of Affective Disorders about a painting in his collection. The title is "Mania", and the artist is Florencio Yllana, who was born in the Phillippines and currently lives in Brazil. Rybakowski says:

The painting was done in 2001 following the acute manic episode in the course of bipolar mood disorder in the artist. A variety of intensive bright colors, the dragon and human-like creatures stemming from the head of the crawling warrior figure can reflect the flamboyant mood as well as the generation and flight of crazy ideas, characteristic of a manic episode. To my knowledge, this may be the only painting titled “Mania” where the title has been used in the contemporarily correct psychiatric meaning of the word.

HAS A LID AND LEADS AND PLUG BUT POSSIBLY WILL NEED CHECKING BY A ELECTRIAN. I HAVE PLUGGED IT IN, AND SEEMS TO WORK FINE BUT I AM NOT A DOCTOR

117 VOLTS 50-60 CYCLES AC 15 WATTS

APPROX HEIGHT 14CM, APPROX WIDTH 17CM, APPROX LENGTH 39CM

Sadly, bidding on this item has ended1. It sold for the low low price of £41.45.

In the journal Anesthesiology, Bause (2010) reflects on the history of the Brain Wave Synchronizer:

After observing how some radar technicians had become “transfixed” by rhythmic flashing dots on their radar screens, inventor Sidney Schneider designed his Brain Wave Synchronizer (BWS) to hypnotize by visually stimulating subjects at frequencies mimicking those of their alpha, beta, or delta brainwaves. In 1959 Schneider and hypnotist-obstetrician William Kroger, M.D., published their use of the BWS in prenatal classes for thousands of women prior to its use as an “electronic aid for hypnotic induction” during labor and delivery [Kroger & Schneider, 1959]. Four years later, Chicago anesthesiologist Max S. Sadove, M.D., published his work on how BWS-induced hypnosis could reduce anesthetic agent requirements during general anesthesia [Sadove, 1963]. By 1994 the BWS would be cited for causing epileptic seizures in a patient.

The modern brainwave synchronization or "brainwave entrainment" industry makes a lot of unsubstantiated claims to sell its devices. But discussing the peer-reviewed evidence on this will be a longer post for another time...

ScienceDaily (Jan. 10, 2011) — Carnegie Mellon University researchers have found that within the brain's neocortex lies a subnetwork of highly active neurons that behave much like people in social networks. Like Facebook, these neuronal networks have a small population of highly active members who give and receive more information than the majority of other members, says Alison Barth, associate professor of biological sciences at Carnegie Mellon and a member of the Center for the Neural Basis of Cognition (CNBC). By identifying these neurons, scientists will now be able to study them further and increase their understanding of the neocortex, which is thought to be the brain's center of higher learning.

In today's hypercompetitive world of limited funding and ever more constricted attention spans, gaining an edge in visibility requires the use of Facebook metaphors. Just ask the amygdala, queen of neuroFacebook for a fortnight.

Barth and colleagues were able to see that the fos-expressing neurons weren't more active because they were intrinsically more excitable; in fact, the neurons seemed to be calmer or more suppressed than their neighboring, inactive neurons. What made them more active was their input.

According to Barth, it seems that this active network of neurons in the neocortex acts like a social network. There is a small, but significant, population of neurons that are more connected than other neurons. These neurons do most of the heavy lifting, giving and receiving more information than the rest of the neurons in their network.

"It's like Facebook. Most of your friends don't post much -- if at all. But, there is a small percentage of your friends on Facebook who update their status and page often. Those people are more likely to be connected to more friends, so while they're sharing more information, they're also receiving more information from their expanded network, which includes other more active participants," Barth said.

Scientists and writers love to compare brains to whatever the cool new technology is. Your brain is a steam engine! Your brain is a telephone! A calculator! A computer! And now, in 2011? Your brain is like Facebook, of course.

. . .

There you have it: Your brain is Facebook (or, if you're stupid, MySpace), and your neurons are social networkers. I guess this makes Mark Zuckerberg... God?

Obviously, the arrival of a new metaphor for the brain probably says more about what technologies we consider important than about the way the brain works. (Not to mention the PR tactics of researchers hoping for a little press.) But it's interesting to note that Facebook—and "social networking" in general—has that kind of brain-metaphor cutting-edge currency.

Unbiased methods to assess the firing activity of individual neurons in the neocortex have revealed that a large proportion of cells fire at extremely low rates (<0.1 Hz), both in their spontaneous and evoked activity. Thus, firing in neocortical networks appears to be dominated by a small population of highly active neurons. Here, we use a fosGFP transgenic mouse to examine the properties of cells with a recent history of elevated activity. FosGFP-expressing layer 2/3 pyramidal cells fired at higher rates compared to fosGFP(-) neurons, both in vivo and in vitro. Elevated activity could be attributed to increased excitatory and decreased inhibitory drive to fosGFP(+) neurons. Paired-cell recordings indicated that fosGFP(+) neurons had a greater likelihood of being connected to each other. These findings indicate that highly active, interconnected neuronal ensembles are present in the neocortex and suggest these cells may play a role in the encoding of sensory information.

The amygdala is a subcortical structure located within the medial temporal lobes. It consists of a number of different nuclei, or collections of neurons delineated by commonalities in morphology and connectivity. The amygdala is best known for major roles in fear conditioning (Paré et al., 2004) and responding to emotional stimuli more generally (Phelps & LeDoux, 2005), but its functions extend beyond that.

A new study by Bickart and colleagues (2010) examined the relationship between the overall size of the amygdala in a group of 58 volunteers and the number of people in each person's social network. The authors observed a direct correlation between the two: the larger the amygdala, the larger the social network. Why did they expect such a finding? The "social brain hypothesis" (Dunbar, 1998) is cited as providing general evidence in favor of increased brain size in more social animals. However, the major references that motivated the specific hypothesis about the amygdala are book chapters, which seemed rather weak and unscholarly to me.

Predictably, a number of silly headlines appeared in the popular press...

Got a big social network? Then you probably have a large amygdala, according to a new study that found a connection between the size of this brain region and the number of social relationships a person has. The complexity of those relationships — as measured by the number of people who occupied multiple roles in a social network such as being simultaneously a friend and a co-worker — was also linked with amygdala size.

The number of Facebook friends you have is correlated to the size of your amygdala, the center used to process the memory of your emotional reactions in your brain, according to a new study published in Nature Neuroscience. The volume of your amydala has been connected to the size of the circle of those you come in contact with even with nonhuman primate species before, so Kevin Bickart and his coauthors took the idea and tested it out on people who interact with people on Facebook.

Does the Amygdala Have a Social Network?

First of all, the size of the amygdala has absolutely nothing to do with Facebook or any other contemporary social networking site. The scale for quantifying social network size and complexity was taken from a 1997 paper on Social Ties and Susceptibility to the Common Cold (Cohen et al., 1997), which in turn cited a book chapter from 1991. There was no such thing as Facebook or Myspace in 1997, only Geocities (1994) and Tripod.com (1995). As for the history of online communities, The WELL was launched in 1985 as a bulletin board system and could be considered as a proto-social networking site.

So who was included in Cohen et al.'s (1997) definition of a social network? One requirement was that the participant spoke to the individual in person or on the phone at least once every two weeks:

The Social Network Index assesses participation in 12 types of social relationships. These include relationships with a spouse, parents, parents-in-law, children, other close family members, close neighbors, friends, workmates, schoolmates, fellow volunteers (eg, charity or community work), members of groups without religious affiliations (eg, social, recreational, or professional), and members of religious groups. One point is assigned for each type of relationship (possible score of 12)1 for which respondents indicate that they speak (in person or on the phone) to someone in that relationship at least once every 2 weeks. The total number of persons with whom they speak at least once every 2 weeks (number of network members) was also assessed.

Results for the amygdalar correlations with social network size and complexity were nearly identical, so the authors focused on the former in the paper. Importantly, amygdala volume did not correlate with life satisfaction or the perceived quality of the relationships. Basically, you could have a large social network that is not of your own choosing. One participant could have a large family, many co-workers, intrusive neighbors, and few real friends, while another is gregarious and parties with different groups of friends every night of the week. This particular study does not distinguish between the two.

Were any other parts of the brain correlated with social network size? No! [which I find hard to believe]. For the entire group of 58 participants, no significant results were observed in other subcortical regions (i.e., hippocampus[which served as a control region], brainstem, nucleus accumbens, ventral diencephalon, thalamus, caudate, putamen, and globus pallidus). An exploratory whole-brain analysis of cortical thickness did not reveal any correlations at conventional levels of significance.

Are we supposed to believe that only one area of the brain is involved in maintaining social networks? I think not. Even within the article, subgroups of participants (i.e., males, all older subjects)2 showed correlations between hippocampal volume and social network characteristics. This makes intuitive sense, as a better memory might be helpful in keeping track of large numbers of people.

What happens to people born without amygdalae due to Urbach-Wiethe disease, a rare genetic disorder? Does "the woman without fear" (and without amygdalae) have a tiny social network? How about other patients with amygdala damage? Anecdotal evidence suggests they can have close ties with their families and can even become more social after their brain injuries.3 Furthermore, Amaral et al. (2003) suggest that

...the effects of amygdala lesions in the adult and infant macaque monkey do not support a fundamental role for the amygdala in social behavior.

So small or absent amygdalae may not be a complete disaster.

But Is Bigger Better?

Findings from our study provoke the question, “Is a bigger amygdala better?” To answer this question, we must consider what “bigger” means and what a bigger amygdala might be “better” for. Striedter suggests that bigger means better connected, so that a brain region with more volume (in cross-species or within species comparisons) has an enhanced ability to modulate processing in its target regions. From cross-species comparisons in nonhuman primates, researchers propose that a bigger amygdala might provide processing advantages for visual signals from conspecifics...

...Yet it is far from clear that the cross-species comparisons can be generalized to infer that a bigger amygdala is better in humans, particularly when it comes to social functioning.

When Bigger Is NOT Better

One prominent example is the finding of larger amygdalae in children (and adults) with autism (Howard et al., 2000; Mosconi et al., 2009). However, the literature on this issue is variable (and voluminous), so I won't discuss it further here. More consistent are observations of increased amygdala volumes in generalized anxiety disorder (Etkin et al., 2009; Schienle et al., 2010). In rats, chronic stress causes hypertrophy (enhanced dendritic arborization) of pyramidal and stellate neurons in the basolateral nucleus of the amygdala (Vyas et al., 2002).

Like often in psychiatric research, these findings seem to be contradictory and thus frustrating at first glance. However, if a dimensional rather than a categorical approach is chosen, all these findings might be integrated based on the assumption that the amygdala volume status might reflect the dominant mode of emotional information processing. Psychopathological features such as depressed mood, anhedonia, lack of drive, phobic anxiety, and rumination might characterize a mode of emotional information processing that is associated with enlarged amygdala volumes, whereas symptoms like emotional instability, dysphoria, irritability, aggression, and psychotic anxiety might go along with reduced amygdala volumes.

Correlation does not equal causation. If the findings are replicable, we don't know if having a large social network increases the size of the amygdala [perhaps due to the stress and anxiety such social pressures entail?], or if having a hefty amygdala causes one to form a large social network.

1 The notion that any one person could fulfill all 12 social roles is absurd. How can anyone simultaneously be a spouse, parent, parent-in-law, child, other close family member, close neighbor, friend, workmate, schoolmate, fellow volunteer, member of a group without religious affiliations, AND member of a religious group?? Obviously, some of these are mutually exclusive.

2 The 58 participants were a diverse group ranging in age from 19-83 yrs (mean = 52.6), which I found strange for such an exploratory study. The demographics were quite unbalanced as well: males (n=36) vs. females (n=22); young (n=19) vs. old (n=35) [which does not add up to 58].

3 Anecdotal evidence from Sophie Scott:

@sophiescott: it's odd, isn't it. I worked with DR, who had bilateral amygdala damage. Hard to assess her network but she was very close...

@sophiescott: ...with her extended family. Another amygdala patient, SE, had become very social since his head injury.

@sophiescott: there were clear effects of their brain damage on their actual social interactions, but they still had them.

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.